Ethacrynic acid (EA) ad its cysteine adduct (CEA), furosemide (FUR) and bumetanide (BUM) are "loop" diuretics. They all produce ototoxicity as a side effect. EA is the most extensively studied of these drugs. It produces one or more of the following effects in the guinea pig, rat, cat and dog: 1.) reduction in hearing, 2.) N1 depression, 3.) cochlear microphonic (CM) depression, 4.) reduction of the positive endolymphatic DC potential (EP), 5.) alteration of endolymph ionic composition and 6.) damage to the cochlear outer hair cells and/or stria vascularis. However, the primary cochlear site and mechanism of ototoxic action of EA have yet to be elucidated because of differences in the responses of the different species of animals to EA and due to the lack of correlative studies investigating what effects equal doses of EA have on the various cochlear potentials and endolymph ionic composition in the same species of animals. Therefore, the primary objective of this research proposal is to ascertain the primary cochlear site and mechanism of ototoxic action of EA, CEA, FUR and BUM in the cat and guinea pig by determining: 1.) whether ototoxicity, as reflected by different amounts of N1 depression produced by these diuretics, is correlated with drug-induced changes in: a) CM responses to 1 and 8 kHz tones, b) EP and/or c) endolymph ionic composition, 2.) whether propranolol, which blocks alteration of endolymph ionic composition produced by FUR without affecting FUR- induced reduction of EP, has any effect on changes in N1, C, EP and endolymph ionic composition produced by EA, CEA and BUM or on changes in N1 and CM produced by FUR, and 3.) whether intra-cochlear injection (scala tympani and media) of cyclic AMP has any effect on those diuretic-induced cochlear changes which are affected by propranolol. N1 and CM responses to click and pure tone stimuli, respectively will be monitored using round window membrane recording techniques. Double- barreled micropipettes will be used for monitoring EP, sampling of endolymph and scala media injections (their tips will be passed through the basilar membrane after removal of the round window membrane). Single-barreled micropipettes will be used for scala tympani injections.